Project Summary The premise of this R21 is that we overlooked a dendritic event in our recent, axon-focus study on cerebellar degeneration in the dysmyelinating Shiverer mouse (Joshi et al., 2015). In the Shiverer cerebellum, we found a parallel increase in SNPH and two forms of cerebellar neurodegeneration, Purkinje cell death and axonal injury, and that genetic deletion of SNPH protects both forms of neurodegeneration. Because SNPH is an axon-specific anchor for mitochondria, we focused our 2015 study on axons and proposed that SNPH upregulation at axons causes mitochondrial traffic congestion that first kills axons then secondarily leads to neuronal death. Deletion of SNPH is protective primarily by preventing axonal death. However, when we re- examined the dendritic layers of Purkinje cells in the Shiverer cerebellum intermingled with densely packed presynaptic axons with the expected upregulation of SNPH, we discovered upon careful 3-D confocal examination that SNPH regulation also occurs in dendrites. This is a total surprise, and may constitute the first demonstrated case that this prominent, axon-specific mitochondrial anchor can lose spatial specificity in pathology and intrudes into the dendritic compartment. The goal of this R21 is to examine if dendritic SNPH intrusion has pathologic consequences that independently kill neurons unrelated to axonal injury. In Aim #1, we will use complementary molecular approaches in addition to the standard 3-D confocal methodology to prove that dendritic SNPH intrusion is not an artifact. In Aim #2, we will demonstrate that dendritic SNPH intrusion is not an innocuous epiphenomenon but can sensitize neurons to excitotoxicity. Conclusion - Given the novelty of this discovery we designed the two aims to be very limited in scope: Eliminating Artifact in Aim #1 and Establishing Causality in Aim #2. Success will engender a future RO1 to elucidate mechanisms of how dendritic SNPH intrusion kills neurons, possibly opening up a completely new category of dendritic pathology in the field of neurodegenerative diseases.